TNF ligand-receptor interactions serve diverse functions in immune system regulation. Fas, a member of the TNF receptor family is an important regulator of lymphocyte homeostasis and can cause systemic autoimmunity when genetically mutated. Although a number of signaling proteins mediating TNF receptor signals have been identified, the cell biology of receptor signaling: where signaling events take place within the cell and whether subcellular localization plays a role in regulating TNF receptor signaling, remains relatively unknown. Understanding this process is important for devising better ways to modulate signaling through these receptors for therapeutic goals. In previous work, we established that TNF receptors must pre-associate into multimeric complexes to signal efficiently. Work in this project aims to characterize the subcellular localization and trafficking of disease-relevant TNF-family receptors both before and after ligand engagement with the aim of eventually manipulating TNF-receptor family trafficking for therapeutic goals in immune-mediated disease states. We are currently studying three main topics in this project: (1) How TCR signals lead to enhanced sensitivity to Fas mediated apoptosis in CD 4(+) T cells; (2) In collaboration Dan Kastner?s lab in NIAMS, we are studying the effects of TNFR1 mutations in the TNFR1 associated periodic fever syndrome (TRAPS) on receptor self-association, trafficking, and stimulation of pro-inflammatory vs. apoptotic signals; and (3) the role of Wiskott-Aldrich protein (WASP) on TCR-mediated apoptosis of activated T cells